Forced use of the impaired forelimb in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of Parkinson's disease, ameliorates behavioral asymmetry and restores dopamine (DA) content in the striatum when commenced immediately after neurotoxic insult. However, the mechanism by which forced-limb use improves behavioral and neurochemical functioning is unknown. Although forced impaired limb use has positive effects on the compromised brain, it can be regarded as a form of restraint stress. Thus, like other stressful stimuli, we might predict that casting the forelimb of animals will stimulate the hypothalamic-pituitary-adrenal axis (HPA axis). Stimulation of the HPA axis results in the release of peptides (e.g. corticotrophin-releasing) into the portal bloodstream where they are transported to the anterior and intermediate lobe of the pituitary stimulating the release of several peptides derived from pro-opiornelanocortin [e.g. adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (alpha, beta and gamma-MSH) and ACTH4-10]. ACTH stimulates the adrenal cortex to release corticosterone (CORT). My preliminary data indicates that unilateral forelimb casting produces an increase in circulating CORT levels and GDNF and BDNF protein levels in the striatum. Thus, I propose to explore one aspect of the manner in which an exercise-trophic-factor-neuroprotection link might occur. Specifically, I will examine the impact of forced exercise on peptides whose release can be initiated through stimulation of the HPA axis. I will focus on ACTH related peptides (i.e., ?-MSH and CORT). Although these peptides and the associated HPA axis are most commonly associated with stress and are usually thought of as being toxic, I will outline evidence that in fact activation of the HPA axis can also serve a critical neuroprotective function and that a better understanding of this function may lead to novel and important strategies for the treatment of PD Thus, the overall goal of the present proposal is to examine the impact of forced forelimb use on peptides whose release can be initiated through activation of the HPA axis and their role in forced limb use-induced protection. To achieve this goal I propose 2 specific aims: (1) determine the impact of forced limb use on CORT levels and whether there is a causal relationship between CORT levels, neurotrophic factor expression, and forced use-induced neuroprotection in a 6-OHDA rodent model of PD and (2) determine the relationship between forced limb use-induced neuroprotection and the increased expression of specific melanocortins. A better understanding of the mechanism by which exercise protects against 6-OHDA neurotoxicity holds great promise to provide insights into the development of such therapies, including offering a rational basis for physical therapy and targets of drug discovery.